1. Field of the Invention
The present invention relates generally to novel palladium complexes and pharmaceutical compositions comprising same. In addition, a method for the preparation of novel palladium complexes is disclosed. Also disclosed is a method for the treatment of tumors comprising administering the novel palladium complexes of the present invention and a method for the treatment of psoriasis comprising administering the novel palladium complexes of the present invention.
2. Related Art
A number of researchers have studied the role that nucleic acids play in tumorigenesis. Although electron reduction of single nucleotides have been reported in, for example, Reichard, "From RNA to DNA, Why So Many Ribonucleotide Reductases?" Science 260:1773-1777 (Jun. 18, 1993); and Hamilton et al., "Cobamides and Ribonucleotide Reduction VII Cobalt(II)alamin as a Sensitive Probe for the Active Center of Ribonucleotide Reductase," Biochemistry 10(2):347-355 (1971), previous reviews of nucleic acids and their role in tumorigenesis make no mention of reactions or substances which result in the electron reduction of DNA or RNA. Townsend et al. (ed), Nucleic Acid Chemistry, Part 3, Wiley Interscience, New York (1986); Saenger, Principles of Nucleic Acid Structure, Springer-Verlag, New York (1984); Walker, "Nucleic Acids," Methods in Molecular Biology, vol. 2, Humana Press, Clifton, N.J. (1984); Grossman et al. (ed), "Nucleic Acids - part 1," Methods in Enzymology, vol. 65, Academic Press, New York (1980); Fasman (ed), "Nucleic Acids," Handbook of Biochemistry and Molecular Biology (3d), vol. 1, CRC Press, Cleveland, Ohio (1975); Blackburn et al. (ed), Nucleic Acids in Chemistry and Biology, IRL Press, Oxford Univ. Press (1990).
The prevailing view of tumorigenesis today is that it may be treated by site-specific regulation, such as by a repressor protein, at proto-oncogene sites. Such proto-oncogene sites are different for each type of tumor being treated and an extensive effort is required in order to pursue this method of treatment for an individual patient.
In 1969 McMullen described a model of the electrostatic free energy of nucleic acids. McMullen, "The Electrostatic Free Energy of Macromolecular Systems," Electronic Aspects of Biochemistry, Annals N.Y. Acad. Sci., Vol. 158, Art. 1,223-239 (May 1969). Purugganan et al. in 1988 described the electron energy interactions of DNA. Purugganan et al., "Accelerated Electron Transfer Between Metal Complexes Mediated by DNA," Science 241:1645-1649 (Sep. 23, 1988).
The first redox regulation of the transcription of the proto-oncogenes c-fos and c-jun was reported in 1990 in a landmark paper by Abate et al., "Redox Regulation of Fos and Jun DNA-Binding Activity in Vitro," Science 249:1157-1161 (Sep. 7, 1990). Abate et al. had previously identified a nuclear factor that stimulates the DNA-binding activity of fos and jun in vitro. This factor did not bind to the fos-jun complex or to the DNA regulatory element known as the activator protein-1 (AP-1) binding site, thereby suggesting that it regulated DNA-binding activity indirectly. The authors hypothesized that the nuclear factor reduces a critical cysteine residue in fos and jun that is required for DNA-binding activity. It was believed that one or more cysteine residues in fos and jun are important for DNA binding and that reduction is required for association with DNA. Abate et al. at 1158. The findings of Abate et al. thus suggested that modification of the redox state of fos and jun may contribute to the formation of specific protein-DNA complexes. The bacterial transcriptional regulatory protein, Oxy R, which regulates gene expression in response to oxidative stress, was found to change DNA-binding specificity depending on the redox state. Thus, regulation by reduction-oxidation was believed to be a mechanism of control for certain transcription factors.
Recently, Shaw et al. studied the free energy of formation of relaxed trefoil and figure-eight DNA knots. Supercoiled trefoil DNA knots were also evaluated. The authors found that the presence of a knot in a relaxed or supercoiled DNA ring is associated with a substantial free energy cost. Furthermore, in enzyme-catalyzed reactions that yield knotted products, this free energy cost must be compensated for by a favorable free energy term, such as that derived from protein-DNA interactions. Shaw et al., "Knotting of a DNA Chain During Ring Closure," Science 260:533-536 (Apr. 23, 1993).
In spite of the above-described research relating to tumorigenesis to date, the conventional methods for the treatment of tumors in individual patients have not met with resounding success. Thus, the search for a new method or methods for the treatment of tumors continues. Likewise, there are other disease states and conditions, such as psoriasis, which have long sought a safe and effective method of treatment.